Anticoagulant Rodenticide Toxicity to Non-target Wildlife Under Controlled Exposure Conditions

  • Barnett A. RattnerEmail author
  • F. Nicholas Mastrota
Part of the Emerging Topics in Ecotoxicology book series (ETEP, volume 5)


Much of our understanding of anticoagulant rodenticide toxicity to non-target wildlife has been derived from molecular through whole animal research and registration studies in domesticated birds and mammals, and to a lesser degree from trials with captive wildlife. Using these data, an adverse outcome pathway identifying molecular initiating and anchoring events (inhibition of vitamin K epoxide reductase, failure to activate clotting factors), and established and plausible linkages (coagulopathy, hemorrhage, anemia, reduced fitness) associated with toxicity, is presented. Controlled exposure studies have demonstrated that second-generation anticoagulant rodenticides (e.g., brodifacoum) are more toxic than first- and intermediate-generation compounds (e.g., warfarin, diphacinone), however the difference in potency is diminished when first- and intermediate-generation compounds are administered on multiple days. Differences in species sensitivity are inconsistent among compounds. Numerous studies have compared mortality rate of predators fed prey or tissue containing anticoagulant rodenticides. In secondary exposure studies in birds, brodifacoum appears to pose the greatest risk, with bromadiolone, difenacoum, flocoumafen and difethialone being less hazardous than brodifacoum, and warfarin, coumatetralyl, coumafuryl, chlorophacinone and diphacinone being even less hazardous. In contrast, substantial mortality was noted in secondary exposure studies in mammals ingesting prey or tissue diets containing either second- or intermediate-generation compounds. Sublethal responses (e.g., prolonged clotting time, reduced hematocrit and anemia) have been used to study the sequelae of anticoagulant intoxication, and to some degree in the establishment of toxicity thresholds or toxicity reference values. Surprisingly few studies have undertaken histopathological evaluations to identify cellular lesions and hemorrhage associated with anticoagulant rodenticide exposure in non-target wildlife. Ecological risk assessments of anticoagulant rodenticides would be improved with additional data on (i) interspecific differences in sensitivity, particularly for understudied taxa, (ii) sublethal effects unrelated to coagulopathy, (iii) responses to mixtures and sequential exposures, and (iv) the role of vitamin K status on toxicity, and significance of inclusion of supplemental vitamin K or menadione (provitamin) in the diet of test organisms. A more complete understanding of the toxicity of anticoagulant rodenticides in non-target wildlife would enable regulators and natural resource managers to better predict and even mitigate risk.


Acute oral toxicity Adverse outcome pathway Biomarkers Coagulopathy Chronic exposure studies Interspecific sensitivity Research Needs Risk assessment Secondary exposure studies Dietary toxicity studies Sublethal effects and responses Vitamin K status 



This manuscript was subjected to review by USEPA’s Office of Pesticide Programs and was approved for submission. Approval does not signify that the contents reflect the views of USEPA. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.


  1. Allen DG, Waters MD (2013) Reducing, refining and replacing the use of animals in toxicity testing. Royal Society of Chemistry, Cambridge, 362 ppCrossRefGoogle Scholar
  2. Anderson JL, Horne BD, Stevens SM, Grove AS, Barton S, Nicholas ZP, Kahn SFS, May HT, Samuelson KM, Muhlestein JB, Carlquist JF (2007) Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 116:2563–2570Google Scholar
  3. Andrew DJ (2014) Acute systemic toxicity: oral, dermal and inhalation exposures. In: Allen DG, Waters MD (eds) Reducing, refining and replacing the use of animals in toxicity testing. Royal Society of Chemistry, Cambridge, pp 187–214Google Scholar
  4. Ashton AD, Jackson WB, Peters H (1986) Comparative evaluation of LD50 values for various anticoagulant rodenticides. Trop Pest Manag 32:187–197Google Scholar
  5. Askham LR, Poché RM (1992) Biodeterioration of chlorophacinone in voles, hawks and an owl. Mammalia 56:145–150CrossRefGoogle Scholar
  6. Aulerich RJ, Ringer RK, Safronoff J (1987) Primary and secondary toxicity of warfarin, sodium monofluoroacetate, and methyl parathion in mink. Arch Environ Contam Toxicol 16:357–366CrossRefGoogle Scholar
  7. Awkerman JA, Raimondo S, Barron MG (2008) Development of species sensitivity distributions for wildlife using interspecies toxicity correlation models. Environ Sci Technol 46:1–18Google Scholar
  8. Bach AU, Anderson SA, Foley AL, Willams EC, Suttie JW (1996) Assessment of vitamin K status in human subjects administered “minidose” warfarin. Am J Clin Nutr 64:894–902Google Scholar
  9. Bailey C, Fisher P, Eason CT (2005) Assessing anticoagulation resistance in rats and coagulation effects in birds using small-volume blood samples. Sci Conserv 249:22 ppGoogle Scholar
  10. Barnes C, Newall F, Ignjatovic V, Wong P, Cameron F, Jones G, Monagle P (2005) Reduced bone density in children on long-term warfarin. Pediatr Res 57:578–581CrossRefGoogle Scholar
  11. Belleville J, Cornillon B, Paul J, Baguet J, Clendinnen G, Eloy R (1982) Haemostasis, blood coagulation and fibrinolysis in the Japanese quail. Comp Biochem Physiol 71A:219–230CrossRefGoogle Scholar
  12. Benzakour O (2008) Vitamin K-dependent proteins: functions in blood coagulation and beyond. Thromb Haemost 100:527–529Google Scholar
  13. Berny P (2011) Challenges of anticoagulant rodenticides: resistance and ecotoxicology. In: Stoytcheva M (ed) Pesticides in the modern world – pests control and pesticides exposure and toxicity assessment. Tech Europe, Rijeka, pp 441–468Google Scholar
  14. Boyle CM (1960) Case of apparent resistance of Rattus norvegicus antagonism between vitamin K and indirect anticoagulants. Nature 188:517CrossRefGoogle Scholar
  15. Brakes CR, Smith RH (2005) Exposure of non-target small mammals to rodenticides: short-term effects, recovery and implications for secondary poisoning. J Appl Ecol 42:118–128CrossRefGoogle Scholar
  16. Brooks MJ, De Laforcade A (2012) Acquired coagulopathies. In: Weiss DJ, Wardrop KJ (eds) Schlam’s veterinary hematology, 6th edn. Wiley-Blackwell, Ames, pp 654–660Google Scholar
  17. Brooks JE, Savarie PJ, Johnston JJ (1998) The oral and dermal toxicity of selected chemicals to brown tree snake (Boiga irregularis). Wildl Res 25:427–435CrossRefGoogle Scholar
  18. Buckle A (2013) Anticoagulant resistance in the United Kingdom and a new guideline for the management of resistant infestations of Norway rats (Rattus norvegicus Berk.) Pest Manag Sci 69:334–341CrossRefGoogle Scholar
  19. Buitenhuis HC, Soute BAM, Vermeer C (1990) Comparison of the vitamins K1, K2 and K3 as cofactors for the hepatic vitamin K-dependent carboxylase. Biochim Biophys Acta 1034:170–175CrossRefGoogle Scholar
  20. Christopher MJ, Balasubramanyam M, Purushotham KR (1984) Toxicity of three anticoagulant rodenticides to male hybrid leghorns. Z Angew Zool 71:275–281Google Scholar
  21. Committee on Toxicity Testing and Assessment of Environmental Agents (2007) Toxicity testing in the 21st century: a vision and a strategy. National Academy Press, Washington, DC, 217 ppGoogle Scholar
  22. Cox P, Smith RH (1992) Rodenticide ecotoxicology: pre-lethal effects of anticoagulants on rat behaviour. Proc Vert Pest Conf 15:165–170Google Scholar
  23. Crabtree DG, Robison WH (1952) Warfarin and its effect on some wildlife species. Trans No Am Wildl Conf 17:167–173Google Scholar
  24. Dam H (1935) The antihaemorrhagic vitamin of the chick: occurrence and chemical nature. Nature 135:652–653CrossRefGoogle Scholar
  25. Dam H, Schonheyder F, Tage-Hansen E (1936) CLV. Studies on the mode of action of vitamin K. Biochem J 30:1075–1079CrossRefGoogle Scholar
  26. Department for Environment, Food and Rural Affairs (DEFRA) (1987) Evaluation on flocoumafen. Available via Accessed 29 Sept 2015
  27. Domella A, Gatto S, Girardi E, Bandoli G (1999) X-ray structures of the anticoagulants coumatetralyl and chlorophacinone. Theoretical calculations and SAR investigations on thirteen anticoagulant rodenticides. J Mol Struct 513:177–199CrossRefGoogle Scholar
  28. DuVall MD, Murphy MJ, Ray AC, Reagor JC (1989) Case studies on second-generation anticoagulant rodenticide toxicities in nontarget species. J Vet Diagn Invest 1:66–68CrossRefGoogle Scholar
  29. Eason CT, Murphy EC, Wright GRG, Spurr EB (2002) Assessment of risks of brodifacoum to non-target birds and mammals in New Zealand. Ecotoxicology 11:35–48CrossRefGoogle Scholar
  30. Eason CT, Fagerstone KA, Eisemann JD, Humphrys S, O’Hare JR, Lapidge SJ (2010) A review of existing and potential New World and Australasian vertebrate pesticides with a rationale for linking use patterns to registration requirements. Int J Pest Manag 56:109–125CrossRefGoogle Scholar
  31. Eichbaum FW, Slemer O, Zyngier SB (1979) Anti-inflammatory effect of warfarin and vitamin K1. Naunyn Schmiedeberg’s Arch Pharmacol 18:185–190CrossRefGoogle Scholar
  32. Eisemann JD, Swift CE (2006) Ecological and human health hazards from broadcast application of 0.005% diphacinone rodenticide baits in native Hawaiian ecosystems. Proc Vert Pest Conf 22:413–433Google Scholar
  33. Elias DJ, Johns BE (1981) Response of rats to chronic ingestion of diphacinone. Bull Environ Contam Toxicol 27:559–567CrossRefGoogle Scholar
  34. Elmeros M, Christensen TK, Lassen P (2011) Concentrations of anticoagulant rodenticides in stoats Mustela ermine and weasels Mustela nivalis from Denmark. Sci Total Environ 409:2373–2378CrossRefGoogle Scholar
  35. European Chemicals Agency (ECHA) (2003) Refined waiving concept for rodenticides. Available via Accessed 1 Dec 2015
  36. European Chemicals Agency (ECHA) (2014a) Committee for risk assessment opinion proposing harmonised classification labelling at EU level of chlorophacinone. Available via Accessed 4 Dec 2015
  37. European Chemicals Agency (ECHA) (2014b) Committee for risk assessment opinion proposing harmonised classification labelling at EU level of bromadiolone. Available via Accessed 4 Dec 2015
  38. European Chemicals Agency (ECHA) (2014c) Committee for risk assessment opinion proposing harmonised classification labelling at EU level of difenacoum. Available via Accessed 4 Dec 2015
  39. European Union (2010) Directive 98/8/EC concerning the placing of biocidal products on the market. Bromadiolone assessment report. Available via Accessed15 Jan 2015
  40. European Union (2012) Regulation (EU) No 528/2012 of the European Parliament and of the Council of 22 May 2012 concerning the making available on the market and use of biocidal products. Off J Eur Union L167 55, pp 1–123Google Scholar
  41. Evans J, Ward AL (1967) Secondary poisoning associated with anticoagulant-killed nutria. J Am Vet Med Assoc 151:856–861Google Scholar
  42. Fisher DD, Timm RM (1987) Laboratory trial of chlorophacinone as a prairie dog toxicant. Great Plains wildlife damage control workshop proceedings. Rapid City, South Dakota, pp 67–69Google Scholar
  43. Fisher P, O’Connor C, Wright G, Eason CT (2004) Anticoagulant residues in rats and secondary non-target risk. Science for Conservation 188. Department of Conservation, Wellington, 29 ppGoogle Scholar
  44. Furie B, Bouchard BA, Furie BC (1999) Vitamin K-dependent biosynthesis of γ-carboxy- glutamic acid. Blood 93:1798–1808Google Scholar
  45. Godfrey MER (1985) Non-target and secondary poisoning hazards of ‘second generation’ anticoagulants. Acta Zool Fenn 173:209–212Google Scholar
  46. Golden HN, Warner SE, Coffey MJ (2016) A review and assessment of spent lead ammunition and its exposure and effects to scavenging birds in the United States. Rev Environ Contam Toxicol 237:123–191Google Scholar
  47. Goodwin MA, Davis JF, Brown J (1992) Packed cell volume reference intervals to aid in the diagnosis of anemia and polycythemia in young broiler chickens. Avian Dis 36:440–443CrossRefGoogle Scholar
  48. Gray A, Eadsforth CV, Dutton AJ (1994) The toxicity of three second-generation rodenticides to barn owls. Pestic Sci 42:179–184CrossRefGoogle Scholar
  49. Greaves JH, Ayres P (1973) Warfarin resistance and vitamin K requirement in the rat. Lab Anim 7:141–148CrossRefGoogle Scholar
  50. Greaves JH, Cullen-Aryes PB (1988) Genetics of difenacoum resistance in the rat. In: Suttie WH (ed) Current advances in vitamin K research, Elsevier, New York, pp 389–397Google Scholar
  51. Griminger P (1965) Vitamin K activity in chickens: phylloquinone and menadione in the presence of stress agrents. J Nutr 87:337–343Google Scholar
  52. Grolleau G, Lorgue G, Nahas K (1989) Toxicité secondaire, en laboratoire, d’un rodenticide anticoagulant (bromadiolone) pour des prédateurs de rongeurs champêtres: buse variable (Buteo buteo) et hermine (Mustela ermines). Bull OEPP/EPPO Bull 19:633–648Google Scholar
  53. Guddorf V, Kummerfeld N, Mischke R (2014) Methodological aspects of blood coagulation measurements in birds applying commercial reagents—a pilot study. Berl Munch Tierarztl Wochenschr 127:322–327Google Scholar
  54. Hagan EC, Radomski JL (1953) The toxicity of 3-(acetonylbenzyl)-4-hydroxycoumarin (warfarin) to laboratory animals. J Am Pharm Assoc 42:379–382Google Scholar
  55. Hall JG, Pauli RM, Wilson KM (1980) Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 68:122–140CrossRefGoogle Scholar
  56. Hanson HH, Barker NW, Mann FD (1951) Clinical experience with 4-hydroxycoumarin anticoagulant no. 63 and the antagonistic effect of menadione and vitamin K1. Circulation 4:844–853CrossRefGoogle Scholar
  57. Harr KE (2012) Overview of avian hemostasis. In: Weiss DJ, Wardrop KJ (eds) Schlam’s Veterinary Hematology, 6th edn. Wiley-Blackwell, Ames, pp 703–707Google Scholar
  58. Hayes WJ Jr (1967) The 90-dose LD50 and a chronicity factor as measures of toxicity. Toxicol Appl Pharmacol 11:327–335CrossRefGoogle Scholar
  59. Health Canada (2012) New use restrictions for commercial class rodenticides in agricultural settings. Canada Pest Management Regulatory Agency. Available via Accessed 17 Dec 2015
  60. Heÿl CW (1986) Cumatetralyl as an avicide for use against the Cape sparrow. S Afr J Enol Vitic 7:71–75Google Scholar
  61. Hill EF (1994) Acute and subacute toxicology in evaluation of pesticide hazard to avian wildlife. In: Kendall RJ, Lacher TE (eds) Wildlife toxicology and population modeling: integrated studies of agroecosystems. CRC Press, Boca Raton, pp 207–226Google Scholar
  62. Hirota Y, Tsugawa N, Nakagawa K, Suhara Y, Tanaka K, Uchino Y, Takeuchi A, Sawada N, Kamao M, Wada A, Okitsu T, Okano T (2013) Menadione (vitamin K3) is a catabolic product of oral phylloquinone (vitamin K1) in the intestine and a circulating precursor of tissue menaquinone-4 (vitamin K2) in rats. J Biol Chem 288:33071–33080CrossRefGoogle Scholar
  63. Holmes MV, Hunt BJ, Shearer MJ (2012) The role of dietary vitamin K in the management of oral vitamin K antagonists. Blood Rev 26:1–14CrossRefGoogle Scholar
  64. Hone J, Kleba R (1984) The toxicity and acceptability of warfarin and 1080 poison in penned feral pigs. Aust Wildl Res 11:103–111CrossRefGoogle Scholar
  65. Hooker S, Innes J (1995) Ranging behaviour of forest-dwelling ship rats, Rattus rattus, and effects of poisoning with brodifacoum. New Zeal J Zool 22:291–304Google Scholar
  66. Howe AM, Webster WS (1992) The warfarin embryopathy: a rat model showing maxillonasal hypoplasia and other skeletal disturbances. Teratology 46:379–390CrossRefGoogle Scholar
  67. International Programme on Chemical Safety (IPCS) (1995) Anticoagulant rodenticides. Environmental Health Criteria 175. Available via Accessed 26 Nov 2014
  68. Jackson WB, Ashton AD (1992) A review of available anticoagulants and their use in the United States. Proc Vert Pest Conf 15:156–160Google Scholar
  69. James SB, Raphael BL, Cook RA (1998) Brodifacoum toxicity and treatment in a white-winged wood duck (Cairina scutulata). J Zoo Wildl Med 29:324–327Google Scholar
  70. Joermann G (1998) A review of secondary-poisoning studies with rodenticides. Bull OEPP/ EPPO 28:157–176CrossRefGoogle Scholar
  71. Kabat H, Stohlman ER, Smith MI (1944) Hypoprothrombinemia induced by administration of indandione derivatives. J Pharmacol Exp Ther 60:160–170Google Scholar
  72. Kater AP, Peppelenbosch MP, Brandjes DPM, Lumbantobing M (2002) Dichotomal effect of the coumadin derivative warfarin on inflammatory signal transduction. Clin Diagn Lab Immunol 9:1396–1397Google Scholar
  73. Kaukeinen DE (1982) A review of the secondary poisoning hazard potential to wildlife from the use of anticoagulant rodenticides. Proc Vert Pest Conf 10:151–158Google Scholar
  74. Klaassen CD (1986) Principles of toxicology. In: Klaassen CD, Amdur MO, Doull J (eds) Casarett and Doull’s toxicology: the basic science of poisons, 3rd edn. Macmillan Publishing Company, New York, pp 11–32Google Scholar
  75. Knopper LD, Mineau P, Walker LA, Shore RF (2007) Bone density and breaking strength in UK Raptors exposed to second generation anticoagulant rodenticides. Bull Environ Contam Toxicol 78:249–251CrossRefGoogle Scholar
  76. Last JA (2002) The missing link: the story of Karl Paul Link. Toxicol Sci 66:4–6CrossRefGoogle Scholar
  77. LaVoie GK (1990) A study of the anticoagulant brodifacoum to American kestrels (Falco sparverius). In: Proceedings of the 3rd international conference of plant protection in the tropics, Genting Highlands, pp 27–29Google Scholar
  78. Lechevin JC, Poché RM (1988) Activity of LM 2219 (difethialone), a new anticoagulant rodenticide, in commensal rodents. Proc Vert Pest Conf 13:59–63Google Scholar
  79. Lee CH (1994) Secondary toxicity of some rodenticides to barn owls. In: Proceedings of the 4th international conference on plant protection in the tropics, Kuala Lumpur, pp 161–163Google Scholar
  80. Link KP (1959) The discovery of dicumarol and its sequels. Circulation 19:97–107CrossRefGoogle Scholar
  81. Littin KE, O'Connor CE, Gregory NG, Mellor DJ, Eason CT (2002) Behaviour, coagulopathy and pathology of brushtail possums (Trichosurus vulpecular) poisoned with brodifacoum. Wildl Res 29:259–267CrossRefGoogle Scholar
  82. Lund M (1981) Hens, eggs and anticoagulants. Int Pest Control 5:126–128Google Scholar
  83. Lund M, Rasmussen AM (1986) Secondary poisoning hazards to stone martens (Martes foina) fed bromadiolone-poisoned mice. Nord Vet Med 38:241–243Google Scholar
  84. Mackintosh CG, Laas FJ, Godfrey MER, Turner K (1988) Vitamin Kt treatment of brodifacoum poisoning in dogs. Proc Vert Pest Conf 13:86–90Google Scholar
  85. Madden W (2002) Racumin rodenticide – potential environmental impacts on birds. In: Newton I, Kavanagh R, Olsen J, Taylor I (eds) Ecology and conservation of owls. CSIRO Publishing, Collingwood, pp 296–301Google Scholar
  86. Massey G, Valutis L, Marzluff J (1997) Secondary poisoning effects of diphacinone on Hawaiian crows: a study using American crows as surrogates. Report to the U.S. Fish and Wildlife Service, Pacific Islands Office. Sustainable Ecosystems Institute, Meridian. 12 pp.Google Scholar
  87. McDowell LR (2000) Vitamins in animal and human nutrition, 2nd edn. Iowa University Press, Ames, 793 ppCrossRefGoogle Scholar
  88. McLoed L, Saunders G (2013) Pesticides used in the management of vertebrate pests in Australia: a review. NSW Department of Primary Industries. Available via Accessed 5 Jan 2015Google Scholar
  89. Mendenhall VM, Pank LF (1980) Secondary poisoning of owls by anticoagulant rodenticides. Wildl Soc Bull 8:311–315Google Scholar
  90. Mineau P, Baril A, Collins BT, Duffe J, Joerman G, Luttik R (2001) Pesticide acute toxicity reference values for birds. Rev Environ Contam Toxicol 170:13–74Google Scholar
  91. Mosterd JJ, Thijssen HHW (1991) The long-term effects of the rodenticide, brodifacoum, on blood coagulation and vitamin K metabolism in rats. Br J Pharmacol 104:531–535CrossRefGoogle Scholar
  92. Mount ME, Woody BJ, Murphy MJ (1986) The anticoagulant rodenticides. In: Kirk RW (ed) Current veterinary therapy IX small animal practice, 9th edn. WB Saunders, Philadelphia, pp 156–165Google Scholar
  93. Murray M (2011) Anticoagulant rodenticide exposure and toxicosis in four species of birds of prey presented to a wildlife clinic in Massachusetts, 2006–2011. J Zoo Wildl Med 42:88–97CrossRefGoogle Scholar
  94. Naim M, Mohd Noor H, Kassim A, Abu J (2011) Comparison of the breeding performance of the barn owl Tyto alba jacanica under chemical and bio-based rodenticide baiting in immature oil palms in Malaysia. Global Sci Books, Dyn Biochem Process Biotech Mol Biol 5:5–11Google Scholar
  95. Newton I, Wyllie I, Freestone P (1990) Rodenticides in British barn owls. Environ Pollut 68:101–117CrossRefGoogle Scholar
  96. Newton I, Wyllie I, Gray A, Eadsforth CV (1994) The toxicity of the rodenticide flocoumafen to barn owls and its elimination via pellets. Pestic Sci 41:187–193CrossRefGoogle Scholar
  97. O’Connor CE, Eason CT, Endepols S (2003) Evaluation of secondary poisoning hazards to ferrets and weka from the rodenticide coumatetralyl. Wildl Res 30:143–146CrossRefGoogle Scholar
  98. Organisation for Economic and Co-operation and Development Test No. 223 (OECD) (2010) Avian acute oral toxicity test. Available via Accessed 9 Dec 2014
  99. Organisation for Economic Co-operation and Development Test No. 409 (OECD) (1998) Repeated dose 90-day oral toxicity study in non-rodents. Available via Accessed 21 Dec 2015
  100. Organisation for Economic Co-operation and Development Test No. 452 (OECD) (2009) Chronic toxicity studies. Available via Accessed 21 Dec 2015
  101. Pank LF, Hirata DN (1976) Primary and secondary toxicity of anticoagulant rodenticides. U.S. Fish and Wildlife Service, Denver Wildlife Research Center. Unpublished Report, pp 13Google Scholar
  102. Pauli BD, Money S, Sparling DW (2010) Ecotoxicology of pesticides in reptiles. In: Sparling DW, Linder G, Bishop CA, Krest SK (eds) Ecotoxicology of amphibians and reptiles, 2nd edn. CRC Press/Taylor and Francis Group, Boca Raton, pp 203–224CrossRefGoogle Scholar
  103. Pelz H-J, Rost S, Hunerberg M, Fregin A, Heiberg A-C, Baert K, MacNicoll AD, Prescott CV, Walker A-S, Oldenburg J, Muller CR (2005) The genetic basis of resistance to anticoagulant rodenticides. Genetics 170:1839–1847CrossRefGoogle Scholar
  104. Pitt WC, Bersten AR, Shiels AB, Volker SF, Eisenmann JD, Wegmann AS, Howald GR (2015) Non-target species mortality and the measurement of brodifacoum rodenticide residues after a rat (Rattus rattus) eradication on Palmyra Atoll, tropical Pacific. Biol Conserv 185:36–46CrossRefGoogle Scholar
  105. Poché RM (1988) Rodent tissue residue and secondary hazard studies with bromadiolone. Bull OEPP/EPPO Bull 18:323–330CrossRefGoogle Scholar
  106. Poché RM, Mach JJ (2001) Wildlife primary and secondary toxicity studies with warfarin. In: Johnston JJ (ed) Pesticides and wildlife, American Chemical Society symposium series, vol 771, pp 181–195CrossRefGoogle Scholar
  107. Ponczek MD, Gailani D, Doolittle RF (2008) Evolution of the contact phase of vertebrate blood coagulation. J Thromb Haemost 6:1976–1883CrossRefGoogle Scholar
  108. Popov A, Mirkov I, Zolotarevski L, Jovic M, Belij S, Kataranovski D, Kataranovski M (2011) Local proinflammatory effects of repeated skin exposure to warfarin, an anticoagulant rodenticide in rats. Biomed Environ Sci 24:180–189Google Scholar
  109. Prescott CV, Johnson RA (2015) The laboratory evaluation of rodenticides. In: Buckle AP, Smith RH (eds) Rodent pests and their control. CAB International, Boston, pp 155–170Google Scholar
  110. Prescott CV, Buckle AP, Hussain I, Endepols S (2007) A standardized BCR resistance test for all anticoagulant rodenticides. Int J Pest Manag 53:265–272CrossRefGoogle Scholar
  111. Prier RF, Derse PH (1962) Evaluation of the hazard of secondary poisoning by warfarin-poisoned rodents. J Am Vet Med Assoc 140:351–354Google Scholar
  112. Primus T, Wright G, Fisher P (2005) Accidental discharge of brodifacoum baits in a tidal marine environment: a case study. Bull Environ Contam Toxicol 74:913–919CrossRefGoogle Scholar
  113. Radvanyi A, Weaver P, Massari C, Bird D, Broughton E (1988) Effects of chlorophacinone on captive kestrels. Bull Environ Contam Toxicol 41:441–448CrossRefGoogle Scholar
  114. Rattner BA, Horak KE, Warner SE, Johnston JJ (2010) Acute toxicity of diphacinone in Northern bobwhite: effects on survival and blood clotting. Ecotoxicol Environ Saf 73:1159–1164CrossRefGoogle Scholar
  115. Rattner BA, Horak KE, Warner SE, Day DD, Meteyer CU, Volker SF, Eisemann JD, Johnston JJ (2011) Acute toxicity, histopathology, and coagulopathy in American kestrels (Falco sparverius) following administration of the rodenticide diphacinone. Environ Toxicol Chem 30:1213–1222CrossRefGoogle Scholar
  116. Rattner BA, Lazarus RS, Eisenreich KM, Horak KE, Volker SF, Campton CM, Eisemann JD, Meteyer CU, Johnston JJ (2012a) Comparative risk assessment of the first-generation anticoagulant rodenticide diphacinone in raptors. Proc Vert Pest Conf 25:124–130Google Scholar
  117. Rattner BA, Horak KE, Lazarus RS, Eisenreich KM, Meteyer CU, Volker SF, Campton CM, Eisemann JD, Johnston JJ (2012b) Assessment of toxicity and potential risk of the anticoagulant rodenticide diphacinone using eastern screech-owls (Megascops asio). Ecotoxicology 21:832–846CrossRefGoogle Scholar
  118. Rattner BA, Lazarus RS, Elliott JE, Shore RF, van den Brink N (2014a) Adverse outcome pathway and risks of anticoagulant rodenticides to predatory wildlife. Environ Sci Technol 48:8433–8445Google Scholar
  119. Rattner BA, Horak KE, Lazarus RS, Goldade DA, Johnston JJ (2014b) Toxicokinetics and coagulopathy threshold of the rodenticide diphacinone in Eastern screech-owls (Megascops asio). Environ Toxicol Chem 33:74–81Google Scholar
  120. Rattner BA, Horak KE, Lazarus RS, Schultz SL, Abbo BG, Volker SF (2015) Toxicity reference values for chlorophacinone and their application for assessing anticoagulant risk to raptors. Ecotoxicology 24:720–734CrossRefGoogle Scholar
  121. Riedel B, Riedel M, Wieland H, Grün G (1988) Vogeltoxikologische bewertung des einsatzes von delicia-chlorphacinon-kodern in landwirtschaftlichen kulterun. Institut fur Planzenschutzforshung Kleinmachnow der Akademie der Landwirtschaftwissenschoften der DRR 42:48–51Google Scholar
  122. Riegerix R, Tillitt DE (2015) Toxicity of anticoagulant rodenticides in two freshwater fishes to aid test design for Hawaiian triggerfish. Society of environmental toxicology and chemistry-North America 36th annual meeting. Abstract WP206Google Scholar
  123. Riley SPD, Bromley C, Poppenga RH, Uzal FA, Whited L, Sauvajot RM (2007) Anticoagulant exposure and notoedric mange in bobcats and mountain lions in urban southern California. J Wildl Manage 71:1874–1884CrossRefGoogle Scholar
  124. Robinson MH, Twigg LE, Wheeler SH, Martin GR (2005) Effect of the anticoagulant, pindone, on the breeding performance and survival of merino sheep, Ovis aries. Comp Biochem Physiol B 140:465–473CrossRefGoogle Scholar
  125. Salim H, Noor HM, Hamid NH, Omar D, Kasim A (2013) Sub-lethal effects of bromadiolone and chlorophacinone on population and breeding performance of barn owl, Tyto alba in palm oil plantations. Paper proceedings of Agri Animal 2013. International Center for Research and Development, Sri Lanka. pp 243–266Google Scholar
  126. Salim H, Mohd Noor H, Hamid NH, Omar D, Kasim A, Abidin CMRZ (2014) Secondary poisoning of captive barn owls, Tyto alba javanica through feeding rats poisoned with chlorophacinone and bromadiolone. J Oil Palm Res 26:62–72Google Scholar
  127. Saravanan K, Kanakasabai R (2004) Evaluation of secondary poisoning of difethialone, a new second-generation anticoagulant rodenticide to barn owl, Toyo alba Hartert under captivity. Indian J Exp Biol 42:1013–1016Google Scholar
  128. Savarie PJ, Hayes DJ, McBride RT, Roberts JD (1979) Efficacy and safety of diphacinone as a predacide. In: Kenaga EE (ed) Avian and mammalian wildlife toxicology. STP 693 American Society for Testing Materials, Philadelphia, pp 69–79CrossRefGoogle Scholar
  129. Scanes CG (2015) Blood. In: Sturkie’s avian physiology, 6th edn. Elsevier, New York, pp 167–191CrossRefGoogle Scholar
  130. Schmaier AA, Stalker TJ, Runge JJ, Lee D, Nagaswami C, Meriko P, Chen M, Cliché S, Gariépy C, Brass LF, Hammer DA, Weisel JW, Rosenthal K, Kahn ML (2011) Occlusive thrombi arise in mammals but not birds in response to arterial injury: evolutionary insight into human cardiovascular disease. Blood 118:3661–3669Google Scholar
  131. Shearer MJ, Newman P (2008) Metabolism and cell biology of vitamin K. Haemost Thromb 100:530–547Google Scholar
  132. Shearer MJ, Fu X, Booth SL (2012) Vitamin K nutrition, metabolism and requirements: current concepts and future research. Adv Nutr 3:182–195CrossRefGoogle Scholar
  133. Shlosberg A, Booth L (2006) Veterinary and clinical treatment of vertebrate pesticide poisoning – a technical review. Landcare Research, Lincoln, 101 ppGoogle Scholar
  134. Sokoll LJ, Sadowski JA (1996) Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population. Am J Clin Nutr 63:566–573Google Scholar
  135. Stevenson RE, Burton OM, Ferlauto GJ, Taylor HA (1980) Hazards of oral anticoagulants during pregnancy. J Am Med Assoc 243:1549–1551Google Scholar
  136. Thijssen HHW (1995) Warfarin-based rodenticides: mode of action and mechanism of resistance. Pestic Sci 43:73–78Google Scholar
  137. Thomas PJ, Mineau P, Shore RF, Champoux L, Martin PA, Wilson LK, Fitzgerald G, Elliott JE (2011) Second generation anticoagulant rodenticides in predatory birds: probabilistic characterisation of toxic liver concentrations and implications for predatory bird populations in Canada. Environ Int 37:914–920. and corrigendum 40:256Google Scholar
  138. Thomson AE, Squires EJ, Gentry PA (2002) Assessment of factor V, VII and X activities, the key coagulant proteins of the tissue factor pathway in poultry plasma. Br Poultry Sci 43:313–321CrossRefGoogle Scholar
  139. Tie J-K, Stafford DW (2008) Structure and function of vitamin K epoxide reductase. Vitam Horm 78:103–130CrossRefGoogle Scholar
  140. Townsend MG, Fletcher MR, Odam EM, Stanley PI (1981) An assessment of the secondary poisoning hazard of warfarin to tawny owls. J Wildl Manag 45:242–248CrossRefGoogle Scholar
  141. Townsend MG, Bunyan PJ, Odam EM, Stanley PI, Wardall HP (1984) Assessment of secondary poisoning hazard of warfarin to least weasels. J Wildl Manag 45:628–632CrossRefGoogle Scholar
  142. Triplett DA, Harms CS (1981) Procedures for the coagulation laboratory. American Society of Clinical Pathologists, Chicago, 179 ppGoogle Scholar
  143. U.S. Environmental Protection Agency (USEPA) (1998) Reregistration eligibility decision (RED) rodenticide cluster. Office of Prevention, Pesticides and Toxic Substances (7508W). Washington, D.C. 319 ppGoogle Scholar
  144. U.S. Environmental Protection Agency (USEPA) (2004) Potential risks of nine rodenticides to birds and nontarget mammals: a comparative approach. EPA P.2004.27 A. Office of Prevention, Pesticides and Toxic Substances, Washington, DC. 230 pp, Available via Accessed 26 Aug 2016
  145. U.S. Environmental Protection Agency (USEPA) (2011) Risks of non-compliant rodenticides to nontarget wildlife – Background paper for scientific advisory panel on notice of intent to cancel non-RMD compliant rodenticide products. EPA-HQ-OPP-2011-0718-0006. Available via Accessed 26 Aug 2016
  146. U.S. Environmental Protection Agency (USEPA) (2015) ECOTOX User Guide: ECOTOXicology Database System. Version 4.0. Available via http:/ Accessed 23 Dec 2015
  147. van den Berg G, Nauta WT (1975) Effects of anti-inflammatory 2-aryl-1,3-indandiones on oxidative phosphorylation in rat liver mitochondria. Biochem Pharmacol 24:815–821CrossRefGoogle Scholar
  148. Veltmann JR Jr, Ross E, Olbrich SE (1981) The physiological effects of feeding warfarin to poultry. Poult Sci 60:2603–2611CrossRefGoogle Scholar
  149. Vyas NB, Rattner BA (2012) Critique on the use of the standardized avian acute oral toxicity test for first generation anticoagulant rodenticides. Hum Ecol Risk Assess 18:1069–1077CrossRefGoogle Scholar
  150. Vyas NB, Spann JW, Hulse CS, Borges SL, Bennett RS, Torrez M, Williams BI, Leffel R (2006) Field evaluation of an avian risk assessment model. Environ Toxicol Chem 25:1762–1771CrossRefGoogle Scholar
  151. Vyas NB, Lockhart JM, Rattner BA, Kuncir F (2014) Coagulopathy and survival of red-tailed hawks following exposure to the anticoagulant rodenticide Rozol®. Society of Environmental Toxicology and Chemistry-North America 35th Annual Meeting. Abstract MP043Google Scholar
  152. Wallace ME, MacSwiney FJ (1976) A major gene controlling warfarin-resistance in the house mouse. J Hyg 76:73–181CrossRefGoogle Scholar
  153. Watanabe KP, Saengtienchai A, Tanaka KD, Ikenaka Y, Ishizuka M (2010) Comparison of warfarin sensitivity between rat and birds species. Comp Biochem Physiol Part C 152:114–119Google Scholar
  154. Watanabe KP, Kawata M, Ikenaka Y, Nakayama SMM, Ishii C, Darwish WS, Saengtienchai A, Mizukawa H, Ishizuka M (2015) Cytochrome P450-mediated warfarin metabolic ability is not a critical determinant of warfarin sensitivity in avian species: in vitro assays in several birds and in vivo assays in chickens. Environ Toxicol Chem 34:2328–2334Google Scholar
  155. Watt BE, Proudfoot AT, Bradberry SM, Vale JA (2005) Anticoagulant rodenticides. Toxicol Rev 24:259–269CrossRefGoogle Scholar
  156. Webster KH, Harr KE, Bennett DC, Williams TD, Cheng KM, Maisonneuve F, Elliot JE (2015) Assessment of toxicity and coagulopathy in Japanese quail and testing in wild owls. Ecotoxicology 24:1087–1101CrossRefGoogle Scholar
  157. Weigt S, Huebler N, Strecker R, Braunbeck T, Broschard TH (2012) Developmental effects of coumarin and the anticoagulant coumarin derivative warfarin on zebrafish (Danio rerio) embryos. Reprod Toxicol 33:133–141Google Scholar
  158. Weir SM, Yu S, Talent LG, Maul JD, Anderson TA, Salice CJ (2015) Improving reptile ecological risk assessment: oral and dermal toxicity of pesticides to a common lizard species (Sceloporus occidentalis). Environ Toxicol Chem 34:1778–1786CrossRefGoogle Scholar
  159. Weir SM, Yu S, Knox A, Talent LG, Monks JM, Salice CJ (2016) Acute toxicity and risk to lizards of rodenticides and herbicides commonly used in New Zealand. New Zeal J Ecol 40:342–350Google Scholar
  160. Will BH, Usui Y, Suttie JW (1992) Comparative metabolism and requirement of vitamin K in chicks and rats. J Nutr 122:2354–2360Google Scholar
  161. Winn MJ, Clegg JAD, Park BK (1987) An investigation of sex-linked differences to the toxic and to the pharmacological action of difenacoum: Studies in mice and rats. J Pharm Pharmacol 39:219–222CrossRefGoogle Scholar
  162. Witmer GW, Burke PW (2009) Influence of vitamin K-rich plant foods on anticoagulant baiting efficacy in wild house mice, wild Norway rats, and wild black rats. Pac Conserv Biol 15:87–91CrossRefGoogle Scholar
  163. Witmer GW, Snow NP, Moulton RS (2013) The effects of vitamin K1-rich plant foods on the efficacy of the anticoagulant rodenticides chlorophacinone and diphacinone, used against the montane voles (Microtus montanus). Inter J Pest Manag 59:205–210CrossRefGoogle Scholar
  164. Wyllie I (1995) Potential secondary poisoning of barn owls by rodenticides. Pestic Outlook 6:19–25Google Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.U.S. Geological Survey, Patuxent Wildlife Research CenterBeltsvilleUSA
  2. 2.U.S. Environmental Protection Agency, Office of Chemical Safety and Pollution PreventionWashington, DCUSA

Personalised recommendations